Biology subjects

Akter, S.

Publications and source records attributed to Akter, S..

28 records · Page 2Linked to original sources

bioRxiv2021

Biophysical and pharmacokinetic characterization of a small-molecule inhibitor of RUNX1/ETO tetramerization with anti-leukemic effects

Acute myeloid leukemia (AML) is a malignant disease of immature myeloid cells and the most prevalent acute leukemia among adults. The oncogenic homo-tetrameric fusion protein RUNX1/ETO results from the chromosomal translocation t(8;21) and is found in AML patients. The nervy homology region 2 (NHR2) domain of ETO mediates tetramerization; this oligomerization is essential for oncogenic activity. Previously, we identified the first-in-class small-molecule inhibitor of NHR2 tetramer formation, 7.44, which was shown to specifically interfere with NHR2, restore gene expression down-regulated by RUNX1/ETO, inhibit the proliferation of RUNX1/ETO-depending SKNO-1 cells, and reduce the RUNX1/ETO-related tumor growth in a mouse model. However, no biophysical and structural characterization of 7.44 binding to the NHR2 domain has been reported. Likewise, the compound has not been characterized as to physicochemical, pharmacokinetic, and toxicological properties. Here, we characterize the interaction between the NHR2 domain of RUNX1/ETO and 7.44 by biophysical assays and show that 7.44 interferes with NHR2 tetramer stability and leads to an increase in the dimer population of NHR2. The affinity of 7.44 with respect to binding to NHR2 is Klig = 3.95 {+/-} 1.28 M. By NMR spectroscopy combined with molecular dynamics simulations, we show that 7.44 binds with both heteroaromatic moieties to NHR2 and interacts with or leads to conformational changes in the N-termini of the NHR2 tetramer. Finally, we demonstrate that 7.44 has favorable physicochemical, pharmacokinetic, and toxicological properties. Together with biochemical, cellular, and in vivo assessments, the results reveal 7.44 as a lead for further optimization towards targeted therapy of t(8;21) AML.

biophysics↗

bioRxiv2021

Stomatal responses at different vegetative stages of selected maize varieties of Bangladesh under water deficit condition

Drought stress causes stomatal behavior change in most plants. Water deficit condition caused by drought is one of the most significant abiotic factors reducing plant growth, development, reproductive efficiency, and photosynthesis, resulting in yield loss. Maize (Zea mays L.) holds a superior position among all the cereals due to its versatile use in the food, feed, and alcohol industries. A common demonstrative feature of a complex network of signaling pathways led by predominantly abscisic acid under drought conditions is stomatal aperture reduction or stomatal closure, which allows the plant to reduce water loss through the stomatal pore and to sustain a long time on water deficit condition. This study analyses the stomatal density, stomatal closure percentages, and guard cell aperture reduction using a microscopy-based rapid & simple method to compare guard cell response & morphological variations of three hybrid maize varieties viz. BHM (BARI hybrid maize)-7, BHM-9, and BHM-13 developed by Bangladesh Agricultural Research Institute (BARI). A drought treatment was applied to all varieties at two different vegetative stages, vegetative stage 3 (V3) and V5, until they reach V4 and V6, respectively. After drought exposure at the V4 stage, the percentage of closed stomata of BHM-7, BHM-9, and BHM-13 was 21%, 23%, and 33%, respectively. The reduction in the guard cell aperture ratio of BHM-7, BHM-9, and BHM-13 was 14.83%, 10.92%, and 33.85%, respectively. At the V6 stage, for the second set of plants, the closed stomata of BHM-7, BHM-9, and BHM-13 were 18%, 21%, and 34%, respectively. The rate of reduction in guard cell aperture ratio of BHM-7, BHM-9, and BHM-13 was 5.52%, 2.48%, and 38.75%, respectively. Therefore, BHM-13 showed maximum drought adaptation capacity compared to BHM-7 and BHM-9 due to the highest percentage of closed stomata and the highest percentage of reduction in aperture ratio.

plant biology↗

bioRxiv2020

Evolutionary dynamics of SARS-CoV-2 nucleocapsid protein (N protein) and its consequences

The emerging novel coronavirus SARS-CoV-2 has created a global confusing pandemic health crisis that warrants an accurate and detailed characterization of the rapidly evolving viral genome for understanding its epidemiology, pathogenesis and containment. We explored 61,485 sequences of the Nucleocapsid (N) protein, a potent diagnostic and prophylactic target, for identifying the mutations to review their roles in RT-PCR based diagnosis and observe consequent impacts. Compared to the Wuhan reference strain, a total of 1034 unique nucleotide mutations were identified in the mutant strains (49.15%, n=30,221) globally. Of these mutations, 367 occupy primer binding sites including 3-end mismatch to primer-pair of 11 well characterized primer sets. Noteworthy, CDC (USA) recommended N2 primer set contained lower mismatch than the other primer sets. Moreover, 684 amino acid (aa) substitutions located across 317 (75.66% of total aa) unique positions including 82, 21, and 83 of those in RNA binding N-terminal domain (NTD), SR-rich region, and C-terminal dimerization domain (CTD), respectively. Moreover, 11 in-frame deletions were revealed, mostly (n =10) within the highly flexible linker region, and the rest within the NTD region. Furthermore, we predicted the possible consequences of high-frequency mutations ([≥] 20) and deletions on the tertiary structure of the N protein. Remarkably, we observed that high frequency (67.94% of mutated sequences) coevolving mutations (R203K and G204R) destabilized and decreased overall structural flexibility. Despite being proposed as the alternate target to spike protein for vaccine and therapeutics, ongoing nonsynonymous evolution of the N protein may challenge the endeavors, thus need further immunoinformatics analyses. Therefore, continuous monitoring is required for tracing the ongoing evolution of the SARS-CoV-2 N protein in prophylactic and diagnostic interventions.

evolutionary biology↗

bioRxiv2020

The genetic variants analysis of circulating SARS-CoV-2 in Bangladesh.

Genomic mutation of the virus may impact the viral adaptation to the local environment, their transmission, disease manifestation, and the effectiveness of existing treatment and vaccination. The objectives of this study were to characterize genomic variations, non-synonymous amino acid substitutions, especially in target proteins, mutation events per samples, mutation rate, and overall scenario of coronaviruses across the country. To investigate the genetic diversity, a total of 184 genomes of virus strains sampled from different divisions of Bangladesh with sampling dates between the 10th of May 2020 and the 27th of June 2020 were analyzed. To date, a total of 634 mutations located along the entire genome resulting in non-synonymous 274 amino acid substitutions in 22 different proteins were detected with nucleotide mutation rate estimated to be 23.715 substitutions per year. The highest non-synonymous amino acid substitutions were observed at 48 different positions of the papain-like protease (nsp3). Although no mutations were found in nsp7, nsp9, nsp10, and nsp11, yet orf1ab accounts for 56% of total mutations. Among the structural proteins, the highest non-synonymous amino acid substitution (at 36 positions) observed in spike proteins, in which 9 unique locations were detected relative to the global strains, including 516E>Q in the boundary of the ACE2 binding region. The most dominated variant G614 (95%) based in spike protein is circulating across the country with co-evolving other variants including L323 (94%) in RNA dependent RNA polymerase (RdRp), K203 (82%) and R204 (82%) in nucleocapsid, and F120 (78%) in NSP2. These variants are mostly seen as linked mutations and are part of a haplotype observed in Europe. Data suggest effective containment of clade G strains (4.8%) with sub-clusters GR 82.4%, and GH clade 6.4%. HighlightsO_LIWe have sequenced 137 and analyzed 184 whole-genomes sequences of SARS-CoV-2 strains from different divisions of Bangladesh. C_LIO_LIA total of 634 mutation sites across the SARS-CoV-2 genome and 274 non-synonymous amino acid substitutions were detected. C_LIO_LIThe mutation rate of SARS-CoV-2 estimated to be 23.715 nucleotide substitutions per year. C_LIO_LINine unique variants were detected based on non-anonymous amino acid substitutions in spike protein relative to the global SARS-CoV-2 strains. C_LI

genomics↗

bioRxiv2020

Comprehensive annotations of the mutational spectra of SARS-CoV-2 spike protein: a fast and accurate pipeline

In order to explore nonsynonymous mutations and deletions in the spike (S) protein of SARS-CoV-2, we comprehensively analyzed 35,750 complete S protein gene sequences from across six continents and five climate zones around the world, as documented in the GISAID database as of June 24th, 2020. Through a custom Python-based pipeline for analyzing mutations, we identified 27,801 (77.77 % of spike sequences) mutated strains compared to Wuhan-Hu-1 strain. 84.40% of these strains had only single amino-acid (aa) substitution mutations, but an outlier strain from Bosnia and Herzegovina (EPI_ISL_463893) was found to possess six aa substitutions. The D614G variant of the major G clade was found to be predominant across circulating strains in all climates. We also identified 988 unique aa substitution mutations distributed across 660 positions within the spike protein, with eleven sites showing high variability - these sites had four types of aa variations at each position. Besides, 17 in-frame deletions at four major regions (three in N-terminal domain and one just downstream of the RBD) may have possible impact on attenuation. Moreover, the mutational frequency differed significantly (p= 0.003, Kruskal-Wallis test) among the SARS-CoV-2 strains worldwide. This study presents a fast and accurate pipeline for identifying nonsynonymous mutations and deletions from large dataset for any particular protein coding sequence and presents this S protein data as representative analysis. By using separate multi-sequence alignment with MAFFT, removing ambiguous sequences and in-frame stop codons, and utilizing pairwise alignment, this method can derive nonsynonymus mutations (Reference:Position:Strain). We believe this will aid in the surveillance of any proteins encoded by SARS-CoV-2, and will prove to be crucial in tracking the ever-increasing variation of many other divergent RNA viruses in the future.

evolutionary biology↗

bioRxiv2020

Whole genome analysis of four Bangladeshi individuals

Whole-genome sequencing (WGS) is a comprehensive method for analysing entire genomes and this has been instrumental in characterizing the single nucleotide polymorphisms associated with different diseases including cancer, diabetes, cardiovascular diseases and many others. In this paper we undertake a pilot study for sequencing four Bangladeshi individuals and profiling their single nucleotide variants. Our findings shed possible light on specific biological pathways effected by such variants in this population.

genomics↗

bioRxiv2020

Epitope-based chimeric peptide vaccine design against S, M and E proteins of SARS-CoV-2 etiologic agent of global pandemic COVID-19: an in silico approach

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing pandemic of coronavirus disease 2019 (COVID-19), a public health emergency of international concern declared by the World Health Organization (WHO). An immuno-informatics approach along with comparative genomic was applied to design a multi-epitope-based peptide vaccine against SARS-CoV-2 combining the antigenic epitopes of the S, M and E proteins. The tertiary structure was predicted, refined and validated using advanced bioinformatics tools. The candidate vaccine showed an average of [≥] 90.0% world population coverage for different ethnic groups. Molecular docking of the chimeric vaccine peptide with the immune receptors (TLR3 and TLR4) predicted efficient binding. Immune simulation predicted significant primary immune response with increased IgM and secondary immune response with high levels of both IgG1 and IgG2. It also increased the proliferation of T-helper cells and cytotoxic T-cells along with the increased INF-{gamma} and IL-2 cytokines. The codon optimization and mRNA secondary structure prediction revealed the chimera is suitable for high-level expression and cloning. Overall, the constructed recombinant chimeric vaccine candidate demonstrated significant potential and can be considered for clinical validation to fight against this global threat, COVID-19.

microbiology↗

bioRxiv2019

Prediction of condition-specific regulatory maps in Arabidopsis using integrated genomic data

Recent advances in genomic technologies have generated large-scale protein-DNA interaction data and open chromatic regions for multiple plant species. To predict condition specific gene regulatory networks using these data, we developed the Condition Specific Regulatory network inference engine (ConSReg), which combines heterogeneous genomic data using sparse linear model followed by feature selection and stability selection to select key regulatory genes. Using Arabidopsis as a model system, we constructed maps of gene regulation under more than 50 experimental conditions including abiotic stresses, cell type-specific expression, and stress responses in individual cell types. Our results show that ConSReg accurately predicted gene expressions (average auROC of 0.84) across multiple testing datasets. We found that, (1) including open chromatin information from ATAC-seq data significantly improves the performance of ConSReg across all tested datasets; (2) choice of negative training samples and length of promoter regions are two key factors that affect model performance. We applied ConSReg to Arabidopsis single cell RNA-seq data of two root cell types (endodermis and cortex) and identified five regulators in two root cell types. Four out of the five regulators have additional experimental evidence to support their roles in regulating gene expression in Arabidopsis roots. By comparing regulatory maps in abiotic stress responses and cell type-specific experiments, we revealed that transcription factors that regulate tissue levels abiotic stresses tend to also regulate stress responses in individual cell types in plants.

bioinformatics↗

bioRxiv2018

A reverse-transcription/RNase H based protocol for depletion of mosquito ribosomal RNA facilitates viral intrahost evolution analysis, transcriptomics and pathogen discovery.

Studies aimed at identifying novel viral sequences or assessing intrahost viral variation require sufficient sequencing coverage to assemble contigs and make accurate variant calling at low frequencies. Many samples come from host tissues where ribosomal RNA represents more than 90% of total RNA preparations, making unbiased sequencing of viral samples inefficient and highly expensive, as many reads will be wasted on cellular RNAs. In the presence of this amount of ribosomal RNA, it is difficult to achieve sufficient sequencing depth to perform analyses such as variant calling, haplotype prediction, virus population analyses, virus discovery or transcriptomic profiling. Many methods for depleting unwanted RNA or enriching RNA of interest have been devised, including poly-A selection, RNase H based specific depletion, duplex-specific nuclease treatment and hybrid capture selection, among others. Although these methods can be efficient, they either cannot be used for some viruses (i.e. non-polyadenylated viruses), have been optimized for use in a single species, or have the potential to introduce bias. In this study, we describe a novel approach that uses an RNaseH possessing reverse transcriptase coupled with selective probes for ribosomal RNA designed to work broadly for three medically relevant mosquito genera; Aedes, Anopheles, and Culex. We demonstrate significant depletion of rRNA using multiple assessment techniques from a variety of sample types, including whole mosquitoes and mosquito midgut contents from FTA cards. To demonstrate the utility of our approach, we describe novel insect-specific virus genomes from numerous species of field collected mosquitoes that underwent rRNA depletion, thereby facilitating their detection. The protocol is straightforward, relatively low-cost and requires only common laboratory reagents and the design of several small oligonucleotides specific to the species of interest. This approach can be adapted for use with other organisms with relative ease, thus potentially aiding virus population genetics analyses, virus discovery and transcriptomic profiling in both laboratory and field samples.

microbiology↗

bioRxiv2018

The relationship between transmission time and clustering methods in Mycobacterium tuberculosis epidemiology

BackgroundTracking recent transmission is a vital part of controlling widespread pathogens such as Mycobacterium tuberculosis. Multiple methods with specific performance characteristics exist for detecting recent transmission chains, usually by clustering strains based on genotype similarities. With such a large variety of methods available, informed selection of an appropriate approach for determining transmissions within a given setting/time period is difficult.\n\nMethodsThis study combines whole genome sequence (WGS) data derived from 324 isolates collected 2005-2010 in Kinshasa, Democratic Republic of Congo (DRC), a high endemic setting, with phylodynamics to unveil the timing of transmission events posited by a variety of standard genotyping methods. Clustering data based on Spoligotyping, 24-loci MIRU-VNTR typing, WGS based SNP (Single Nucleotide Polymorphism) and core genome multi locus sequence typing (cgMLST) typing were evaluated.\n\nFindingsOur results suggest that clusters based on Spoligotyping could encompass transmission events that occurred over 70 years prior to sampling while 24-loci-MIRU-VNTR often represented two or more decades of transmission. Instead, WGS based genotyping applying low SNP or cgMLST allele thresholds allows for determination of recent transmission events in timespans of up to 10 years e.g. for a 5 SNP/allele cut-off.\n\nInterpretationWith the rapid uptake of WGS methods in surveillance and outbreak tracking, the findings obtained in this study can guide the selection of appropriate clustering methods for uncovering relevant transmission chains within a given time-period. For high resolution cluster analyses, WGS-SNP and cgMLST based analyses have similar clustering/timing characteristics even for data obtained from a high incidence setting.

epidemiology↗